Reciprocal coevolution of tumors and their microenvironments underlies disease progression, yet intrinsic limitations of patient-derived xenografts and simpler cell-based models present challenges ...towards a deeper understanding of these intercellular communication networks. To help overcome these barriers and complement existing models, we have developed a human microphysiological system (MPS) model of the human liver acinus, a common metastatic site, and have applied this system to estrogen receptor (ER)+ breast cancer. In addition to their hallmark constitutive (but ER-dependent) growth phenotype, different ESR1 missense mutations, prominently observed during estrogen deprivation therapy, confer distinct estrogen-enhanced growth and drug resistant phenotypes not evident under cell autonomous conditions. Under low molecular oxygen within the physiological range (~5-20%) of the normal liver acinus, the estrogen-enhanced growth phenotypes are lost, a dependency not observed in monoculture. In contrast, the constitutive growth phenotypes are invariant within this range of molecular oxygen suggesting that ESR1 mutations confer a growth advantage not only during estrogen deprivation but also at lower oxygen levels. We discuss the prospects and limitations of implementing human MPS, especially in conjunction with in situ single cell hyperplexed computational pathology platforms, to identify biomarkers mechanistically linked to disease progression that inform optimal therapeutic strategies for patients.
To independently assess quality of care among patients who died in hospital and whose next-of-kin submitted a letter of complaint and make comparisons with matched controls. To identify whether use ...of a treatment escalation limitation plan (TELP) during the terminal illness was a relevant background factor.
The study was an investigator-blinded retrospective case-note review of 42 complaints cases and 72 controls matched for age, sex, ward location and time of death.
The acute medical and surgical wards of three District General Hospitals administered by NHS Lanarkshire, Scotland.
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Quality of care: clinical 'problems', non-beneficial interventions (NBIs) and harms were evaluated using the Structured Judgment Review Method. Complaints were categorized using the Healthcare Complaints Analysis Tool.
The event frequencies and rate ratios for clinical 'problems', NBIs and harms were consistently higher in complaint cases compared to controls. The difference was only significant for NBIs (P = 0.05). TELPs were used less frequently in complaint cases compared to controls (23.8 versus 47.2%, P = 0.013). The relationship between TELP use and the three key clinical outcomes was nonsignificant.
Care delivered to patients at end-of-life whose next-of-kin submitted a complaint was poorer overall than among control patients when assessed independently by blinded reviewers. Regular use of a TELP in acute clinical settings has the potential to influence complaints relating to end-of-life care, but this requires further prospective study.
Human analysis of research data is slow and inefficient. In recent years, machine learning tools have advanced our capability to perform tasks normally carried out by humans, such as image ...segmentation and classification. In this work, we seek to further improve binary classification models for high-throughput identification of different microstructural morphologies. We utilize a dataset with limited observations (133 dendritic structures, 444 non-dendritic) and employ data augmentation via rotation and translation to enhance the dataset six-fold. Then, transfer learning is carried out using pre-trained networks VGG16, InceptionV3, and Xception achieving only moderate F1 scores (0.801–0.822). We hypothesize that feature engineering could yield better results than transfer learning alone. To test this, we employ a new nature-inspired feature optimization algorithm, the Binary Red Deer Algorithm (BRDA), to carry out binary classification and observe F1 scores in the range of 0.96.
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•A dataset comprising two categories of micrographs has been prepared•Transfer learning has been implemented for micrograph classification•To improve upon the classification accuracy, we perform feature engineering•Feature engineering has been performed using Binary Red Deer Algorithm
Computer modeling; Materials science; Computational materials science
The nonsense‐mediated mRNA decay (NMD) pathway regulates mRNAs that aberrantly terminate translation. This includes aberrant mRNAs and functional natural mRNAs. Natural mRNA degradation by NMD is ...triggered by mRNA features and environmental cues. Saccharomyces cerevisiae encodes multiple proteins with ferric and cupric reductase activity. Here, we examined the regulation by NMD of two mRNAs, FRE1 and FRE2, encoding ferric and cupric reductases in S. cerevisiae. We found that FRE2 mRNAs are regulated by NMD under noninducing conditions and that the FRE2 3′‐UTR contributes to the degradation of the mRNAs by NMD. Conversely, FRE1 mRNAs are not regulated by NMD under comparable conditions. These findings suggest that regulation of functionally related mRNAs by NMD can be differential and conditional.
Gram-negative bacterial septicemia is mediated through binding of lipopolysaccharide (LPS) to mammalian toll-like receptor protein 4 (TLR4). TLR4 and its cognate protein, myeloid differentiation ...factor 2 (MD2) form a heterodimeric complex after binding LPS. This complex induces a cascade of reactions that results in increased proinflammatory cytokine gene expression, including TNFα, which leads to activation of innate immunity. In horses, the immune response to LPS varies widely. To determine if this variation is due to differences in TLR4 or MD2, DNA from 15 healthy adult horses with different TNFα dynamics after experimental intravenous LPS infusion was sequenced across exons of TLR4 and MD2. Haplotypes were constructed for both genes using all identified variants. Four haplotypes were observed for each gene. No significant associations were found between either TNFα baseline concentrations or response to LPS and haplotype; however, there was a significant association (P value = 0.0460) between the baseline TNFα concentration and one MD2 missense variant. Three-dimensional structures of the equine TLR4-MD2-LPS complex were built according to haplotype combinations observed in the study horses, and the implications of missense variants on LPS binding were modeled. Although the sample size was small, there was no evidence that variation in TLR4 or MD2 explains the variability in TNFα response observed after LPS exposure in horses.
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic ...stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.
Cancer survival has improved for the most common cancers. However, less improvement and lower survival has been observed in some groups perhaps due to differential access to cancer care including ...prevention, screening, diagnosis, and treatment.
To further understand contemporary relative cancer survival (one- and five- year), we used survival data from CDC's National Program of Cancer Registries (NPCR) for cancers diagnosed during 2007-2016. We examined overall relative cancer survival by sex, race and ethnicity, age, and county-level metropolitan and non-metropolitan status. Relative cancer survival by metropolitan and non-metropolitan status was further examined by sex, race and ethnicity, age, and cancer type.
Among persons with cancer diagnosed during 2007-2016 the overall one-year and five-year relative survival was 80.6% and 67.4%, respectively. One-year relative survival for persons living in metropolitan counties was 81.1% and 77.8% among persons living in non-metropolitan counties. We found that persons who lived in non-metropolitan counties had lower survival than those who lived in metropolitan counties, and this difference persisted across sex, race and ethnicity, age, and most cancer types.
Further examination of the differences in cancer survival by cancer type or other characteristics might be helpful for identifying potential interventions, such as programs that target screening and early detection or strategies to improve access to high quality cancer treatment and follow-up care, that could improve long-term outcomes.
This analysis provided a high-level overview of contemporary cancer survival in the United States.
Neuroinflammation plays an important role in HIV-associated neurological disorders; however, its role prior to the onset of symptomatic disease is unclear. We imaged microglial activation, the ...hallmark of neuroinflammation, in asymptomatic HIV-infected patients on effective combination ART.
Seven neurologically and cognitively asymptomatic adults with chronic HIV-infection and nine healthy volunteers were investigated with 11C-PK11195 PET, a marker of translocator protein (TSPO) expressed by activated microglia. In the HIV-infected patients, cognitive speed, accuracy and executive function were also assessed. Between-group differences in 11C-PK11195 binding potential were localized throughout the brain with statistical parametric mapping (SPM) and associations between levels of 11C-PK11195 binding and cognitive performance were interrogated using linear regression modelling.
In HIV-infected patients, Statistical parametric mapping detected clusters of significantly increased 11C-PK11195 binding in corpus callosum (P = 0.001), anterior cingulate (P = 0.001), posterior cingulate (P = 0.008) and temporal (P = 0.026) and frontal (P = 0.038) areas. Cognitive functions were intact in the HIV group, however, a significant association between greater 11C-PK11195 binding and poorer executive function performance was observed in the anterior cingulate (P = 0.031), corpus callosum and posterior cingulate (P = 0.001).
Despite effective control of HIV infection, neuroinflammation, as evidenced by the presence of focal cortical areas of activated microglia, occurs in asymptomatic HIV-infected patients and levels correlate with poorer executive performance. Further studies are needed to establish whether detection of activated microglia in HIV-infected patients represents a marker of future neurocognitive decline.
Abstract Objective Endografts (eg, aortic aneurysm device or covered stent) are increasingly being used to temporize or treat arterial and graft infections in inaccessible areas, in patients with ...compromised anatomy, or in the presence of active bleeding or rupture. This summary examines the evidence for “in situ” endografting in the treatment these conditions. Methods A two-level search strategy of the literature (MEDLINE, PubMed, Google Scholar, and The Cochrane Library) was performed for relevant articles listed between January 2000 and December 2015. The review was confined to patients with primary and secondary bacterial or viral arterial infections, with or without fistulization and infection of bypass grafts and arteriovenous accesses. For the purposes of this summary, endografts can be considered to be an aortic aneurysm device or a covered stent. Results There are no societal guidelines. Endografts have been successfully applied to mycotic arterial aneurysms, aortoenteric, aortobronchial, and arterioureteric fistulae, and to anastomotic bleeds secondary to infection. Multiple reports indicate success at the control of hemorrhage in all locations. Short-term outcomes are good, but fatal infection-related complications, especially if antibiotic therapy is halted, are well reported and necessitate a more definitive plan for the long term. Conclusions Stent grafts remain an important and viable option for the treatment of mycotic aneurysms, aortoesophageal and aortobronchial fistulae, and infected pseudoaneurysms in anatomically or technically inaccessible locations. In patients with a short life span (<6 months), no further intervention is generally required. In patients with a predicted life span >6 months, careful consideration should be given to a more definitive procedure. Life-long appropriate antibiotic therapy is strongly recommended for any patient receiving an endograft in an infected field.
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